PROJECT SUMMARY/ABSTRACT Substantial data indicate that general anesthesia (GA) causes neurotoxicity and long-term deficits in learning and memory in young animals. Millions of young human children have GA annually. This is of great public health concern given the possibility that early GA could cause abnormalities in brain and cognitive development that might have lifelong consequences. Although there is great concern that findings from animal studies may apply to humans, limited evidence exists concerning the possible adverse effects on brain and cognitive development of early GA in humans. Studies using neuroimaging techniques are especially limited. Our objective in this proposal is to understand the consequences of GA during early childhood on subsequent brain structure, brain function, and cognition by comparing adolescents with GA during early childhood to otherwise similar control subjects without GA. We will evaluate the effects of GA on magnetic resonance imaging measures of brain tissue volume and composition, white matter integrity, regional brain activity during long-term and working memory tasks, and resting state functional connectivity, as well as cognitive test performance and academic achievement. Our hypotheses, based on our preliminary data, are that early GA will be associated with lower white matter volumes and diminished white matter integrity, memory-related changes in brain activity during long-term and working memory tasks, impaired visual long-term memory recognition, and a higher frequency of very low achievement test scores. The proposed research additionally aims to compare GA occurring at varying ages within the range of birth to 3 years, and accompanying high vs. low invasive procedures. We will focus primarily on children without significant central nervous system problems or potential risk factors that might constitute confounding factors. We additionally hypothesize that to whatever extent the hypotheses stated above are confirmed, the observed effects will be smaller for first GA exposure at older ages, e.g., smaller effects from exposure at 3 years relative to near birth; and be comparable for high vs. low invasive procedures, when other factors such as GA duration and gender are controlled. We also hypothesize that any such effects will increase with increasing GA duration. We will additionally explore influences of comorbidity (i.e., premature birth) and regional anesthesia on consequences of GA. The findings could address potential mechanisms of the brain effects of GA found in animal studies, such as apoptosis of oligodendrocytes and neurons and/or other neurotoxicity that occur during critical developmental periods. The proposed research will help fill a critical gap in knowledge concerning the consequences of GA during early childhood on brain and cognitive development, and provide information about its risks that might change best practices for clinical care of children who have GA.